Surveys show that most men in the United States are interested in using male contraception, yet their options are limited to unreliable condoms or invasive vasectomy. Recent attempts to develop drugs that inhibit sperm production, maturation, or fertilization have had limited success, providing incomplete protection or severe side effects. New approaches to male contraception are needed, but because sperm development is so complex, researchers have struggled to identify parts of the process that can be safely and effectively tinkered with. .

Now, scientists at the Salk Institute have discovered a new way to disrupt sperm production, which is non-hormonal and reversible. The study, published in Proceedings of the National Academy of Sciences (PNAS). on Feb. 20, 2024, implicates a novel protein complex in regulating gene expression during sperm production. The researchers show that treating male mice with a current class of drugs called HDAC (histone deacetylase) inhibitors can disrupt the function of this protein complex and prevent fertility without affecting libido.

“Most experimental male birth control drugs use a hammer mechanism to block sperm production, but ours is much more subtle,” said senior author Ronald Evans, professor, director of the Gene Expression Laboratory and director of the March of Dimes. The chair is called Molecular and Developmental Biology. Seeker. “This makes it a promising therapeutic approach, which we hope to see in development for human clinical trials soon.”

The human body produces millions of new sperm every day. To do this, the sperm stem cells in the testes continuously reproduce themselves, until a signal tells them it’s time to turn into sperm — a process called spermatogenesis. This signal comes in the form of retinoic acid, a byproduct of vitamin A. Pulses of retinoic acid bind to retinoic acid receptors in cells, and when the system is perfectly aligned, it initiates a complex genetic program that transforms stem cells. mature sperm.

Salk scientists found that for this to work, retinoic acid receptors must bind to a protein called SMRT (silencing mediator of retinoid and thyroid hormone receptors). SMRT then recruits HDACs, and this complex of proteins coordinates the expression of sperm-producing genes.

Previous groups have attempted to inhibit sperm production by directly inhibiting retinoic acid or its receptor. But retinoic acid is important for multiple organ systems, so disrupting it throughout the body can lead to a variety of side effects — one reason many previous studies and trials have failed to produce a viable drug. have been Evans and his colleagues instead asked if they could modulate one of the molecules downstream of retinoic acid to produce a more targeted effect.

The researchers first looked at a line of genetically engineered mice previously developed in the lab, in which the SMRT protein had been altered and could no longer bind to retinoic acid receptors. Without this SMRT-retinoic acid receptor interaction, mice were unable to produce mature sperm. However, they showed normal testosterone levels and increased behavior, indicating that their desire to mate was not affected.

To see if they could replicate these genetic findings with pharmacological intervention, the researchers treated normal mice with MS-275, an oral HDAC inhibitor with FDA breakthrough status. By blocking the activity of the SMRT-retinoic acid receptor-HDAC complex, the drug successfully inhibited sperm production without causing obvious side effects.

Another remarkable thing happened after treatment stopped: within 60 days of stopping the pill, the animals’ fertility was fully restored, and all subsequent offspring were developmentally healthy.

The authors say their strategy of blocking molecules downstream of retinoic acid is key to achieving this reversal.

Think of retinoic acid and the sperm-producing genes as two dancers in a waltz. Their rhythms and steps need to be in sync with each other for the dance to work. But if you throw in something that causes Janes to miss a step, the two are suddenly out of sync and the dance falls apart. In this case, the HDAC inhibitor causes the genes to malfunction, which stops the sperm production cycle.

However, if the dancer can find his footing and return to step with his partner, the waltz can be resumed. Similarly, the authors say that removing the HDAC inhibitor allows sperm-producing genes to return to sync with the pulse of retinoic acid, allowing sperm production to resume as desired. is done.

“It’s all about timing,” says co-author Michael Downs, a senior staff scientist in Evans’ lab. “When we add the drug, the stem cells go out of sync with the retinoic acid pulse, and sperm production stops, but as soon as we remove the drug, the stem cells stop retinoic acid and sperm production. Can re-establish your harmony with. Will start again.”

The authors say the drug does not damage sperm stem cells or their genomic integrity. When the drug was present, the sperm stem cells continued to reproduce as stem cells only, and when the drug was later removed, the cells could regain their ability to differentiate into mature sperm.

“When we discovered SMRT and created this mouse line, we weren’t necessarily trying to develop male contraceptives, but when we saw that their fertility was disrupted, we took science into account. were able to follow and discover a potential treatment,” says first author Schuck. Hyun Hong, a staff researcher in Evans’ lab. “This is an excellent example of how Salk’s basic biology research can lead to major translational impacts.”

Other authors include Glenda Castro, Dan Wang, Russell Noffsinger, Annette R. Atkins, and Ruth Tu of Salk, Maureen Kane, Alexandra Folias, and Joseph L. Napoli of UC Berkeley, Paolo Sasson-Corcio of UC Irvine, Dirk Yes included. de Rooij of Utrecht University, and Christopher Liddle of the University of Sydney.

This work was funded by the National Institutes of Health (grants CA265762 and CA220468) and the Next Generation Sequencing and Flow Cytometry Core at Salk, Salk Cancer Center (NCI grant NIH-NCI CCSG: P30 014195).